The saying that politics makes strange bedfellows has gained a new dimension today. In a rare bipartisan effort, two staunchly conservative congressmen, Michele Bachmann and Tom Marino, have joined forces with liberals Karen Bass and Jim McDermott to propose "Justina's Law."

Justina's Law would bar federal funding of any institution that uses wards of the state for medical experimentation. On the surface, this appears to be a law fraught with loopholes. It is possible that mental hospitals could justify forced psychiatric treatment on the grounds that it is usual and customary.

Usual and customary treatment for all mental illnesses (other than schizophrenia, bipolar disorder, and psychosis) consists of therapy (CBT), sedatives, and/or antidepressants. These are not actually treatments, because there are no objective tests for mental disorders. That is because the majority of mental disorders are not illnesses; they are simply a reflection of social conventions and cultural mores of the time. Given the lack of any scientific evidence for the existence of somatoform disorder - an antiquated diagnosis left over from Freudian psychiatry - it would be a stretch to claim that its treatment is anything but experimental.

The treatment Justina was given throughout her stay as a ward of the state was not approved by Justina's parents, who have consistently maintained that the state of Massachusetts experimented on their daughter. Justina's previous diagnosis of mitochondrial disease (an inherited condition also suffered by her sister) was disputed by a neurologist at Boston Children's Hospital. The neurologist re-diagnosed Justina with "somatoform disorder." Her parents were then accused of "medicalizing" her illness. Over the next year, Justina was refused medication for mitochondrial disease, and placed in a locked mental ward. Eventually, the state moved her to foster care. During the 16 months she was a ward of the state, Justina's condition deteriorated until she could no longer walk or stand.

Justina's Law, if passed, could have profound ramifications for the ME/CFS community. Hundreds of children with ME/CFS have been taken from their homes on the basis of psychiatric diagnoses that are just as unsubstantial as somatoform disorder. This law would give legal grounds to parents suing to get their children back. It might even help get some of these pseudo-psychiatric "diagnoses" relegated to the dustbin of history, which is where they belong.

You may use the template letter below................................................................Please support H. R. 4989, "Justina's Law." Justina Pelletier was incarcerated by the state of Massachusetts for over a year based on a psychiatric diagnosis for which there is not one shred of scientific evidence (somatoform disorder). As a result, Justina's disease (mitochondrial disease, a rare inherited disorder) has progressed, and she is no longer able to walk. Justina is not the only child to have suffered this fate. In 2009, Ryan Baldwin, a boy with myalgic encephalomyelitis (aka chronic fatigue syndrome) was taken away from his family in North Carolina and placed in foster care, where he grew steadily worse.

Please prevent more cases like Justina's and Ryan's. Support "Justina's Law."__________________________________________

The bill, H.R. 4989, nicknamed “Justina’s Law”, is a response to the recent case of 16-year-old Justina Pelletier, who was finally released from Boston Children’s Hospital (BCH) back to the care of her family after a 16-month custody battle between the Commonwealth of Massachusetts and Justina’s parents.

BCH and many other hospitals have an internal policy that allows for children who are deemed “wards of the State”, including foster children, to receive treatment or be involved in research that presents great risk even if there is no prospect of any benefit to the child.

“Whether it is one child or thousands, it is our duty to guarantee that children are kept safe from harm while in the custody of their respective states. Not all these children have families like the Pelletiers willing or able to advocate on their behalf. Sixteen months ago, Justina was a figure skater. Today, she cannot stand, sit, or walk on her own. It is unconscionable what happened to Justina, and we must do all we can to prevent it from ever happening again. Removing federal funding from such experimentation is an important first step.” – Rep. Michele Bachmann (MN-06)

"Children need to be loved and cared for, not treated as something to be experimented on. Foster children are particularly vulnerable because they may not have parents to advocate for them. This bill will make it clear that children are blessings, not guinea pigs." – Rep. Karen Bass (CA-37)

“The bonds between children and parents is sacred. The closeness and level of intimate understanding between them transcends our societal constructs. In Justina’s case, she was kept from her loved ones and essentially detained by the hospital and the state. She was lucky to have parents that fought for her and leveraged the support of the media and public officials. Yet too many children do not have parents to speak for them and look out for their health and best interests during times of physical and emotional vulnerability. That fact saddens me. It would sadden any person who knows the power of love and affection. That is why I am proud to support Reps. Bachmann, Bass, and McDermott on this legislation because no child, with parents or not, should be subject to medical experimentation under the legal designation as ward of the state.” – Rep. Tom Marino (PA-10)

“The strength and bravery that Justina Pelletier and her family have shown in the face of incredible hardship is a guidestar for us all. We must act to protect and cherish children in the care of a state and make sure that they are not the subject of risky medical experimentation. I look forward to working with Reps Bachman, Bass, Marino and countless other colleagues from both sides of the aisle to pass Justina’s law as quickly as possible.” – Rep. Jim McDermott (WA-07)

There have been several attempts to gain access to the full results of the Queen Mary University of London's PACE trial under the Freedom of Information Act.

All of these attempts have been quashed. Nonetheless, Mr. Matthees continues to make his case, and make it well. [See below]

There are many reasons to demand that the PACE trial submit its full results, not the least of which is that the published results of the PACE trial are misleading (if not outright tweaked). Bad science is one thing, but the wholesale acceptance of bad science is something else entirely.

With the spate of publicity surrounding the trial, doctors, clinics, and health agencies have uncritically embraced CBT and graded exercise as legitimate treatments for ME/CFS. Here are just a few examples in the US:

Mayo Clinic"The most effective treatment for chronic fatigue syndrome appears to be a two-pronged approach that combines psychological counseling with a gentle exercise program.

Graded exercise. A physical therapist can help determine what types of exercise are best for you. Inactive people often begin with range-of-motion and stretching exercises for just a few minutes a day. If you're exhausted the next day, you're doing too much. Your strength and endurance will improve as you gradually increase the intensity of your exercise over time.

Psychological counseling. Talking with a counselor can help you figure out options to work around some of the limitations that chronic fatigue syndrome imposes on you. Feeling more in control of your life can improve your outlook dramatically."

CDC Toolkit"Cognitive behavioral therapy, or CBT, is an individualized, structured, goal-oriented form of therapy often prescribed to help chronically ill patients cope with illness and develop behaviors and strategies that help improve symptoms. CBT has been shown to be effective for some patients with CFS, but it must be paced, personalized, and tailored to the individual’s level.

Graded exercise therapy (GET) has shown to be very helpful to some CFS patients. Graded activity and exercise is defined as starting from a very low, basic level of exercise and/or activity and gradually increasing it to a level where people can go about their daily life." University of Maryland Medical Center

"Seeing a therapist who is trained in cognitive-behavioral therapy (CBT) can help CFS patients regain a sense of control over their lives. A number of studies [it added] have reported the benefits of a graded exercise program, in which patients gradually perform more intense exercises as their abilities improve. Research has found that most CFS patients who are able to engage in exercise, particularly aerobic exercise, report less fatigue and better daily functioning and fitness. Exercise works best for CFS when combined with CBT and education."...........................

With our most respected agencies and clinics recommending CBT and GET it is no wonder that virtually all of the treatment information found online reflects the results of the PACE trial.

"Two types of therapy appear to benefit CFS patients. One is psychological counseling to help you cope with CFS and improve your mindset. The other is physical therapy. A physical therapist can evaluate you and create an exercise routine for you that gradually increases in intensity. This is known as graded exercise therapy, or GET."Medicinenet"In general the therapy will be a combination of psychological counseling (to help with the day-to-day burden CFS imposes on the patient's life) and mild, guided exercise..."

In short, the PACE trial is more than bad science. It is a piece of propaganda that is directly modeled after the Big Lie: “If you tell a lie big enough and keep repeating it, people will eventually come to believe it." (Joseph Goebbels)

The lie that cognitive behavioral therapy and GET are "the most effective therapies," "appear to help," "are very helpful" for ME/CFS is one that will continue to inform physicians and harm patients as long as the actual results of the PACE trial remain under wraps.

[Please see below for Mr. Matthees' argument for why full disclosure is in the public interest.]_____________________________18 June 2014

Dear Mr Smallcombe / QMUL,

Thank you for the response to FOI 2014/F73, which was refused as exempt under s.40(2) and s.41(1) of the Freedom of Information Act 2000 (FOIA), drawing upon the the Data Protection Act 1998 (DPA), and with references to GMC and MRC guidance: "as the information consists of sensitive medical data provided in confidence by participants in the PACE trial" and cannot be fairly processed by the data controller for purposes other than what it was explicitly collected for. Unfortunately, I am dissatisfied with the response and would like to request an internal review and further clarification with reference to the following:

• It is entirely possible to disclose anonymised trial data without breaching the DPA or fairness of the FOIA, the DPA's definition of personal data cannot be extended to cover situations where the disclosed data does not identify any individual, the disclosure of anonymised data is not a disclosure of personal data even when the data controller holds the key to re-identification, consent is not necessary to release anonymised data when it is unlikely to lead to re-identification, and the DPA does not require anonymisation to be completely risk free but mitigated until the risk of re-identification is remote. [1] This FOI request involves a heavily redacted dataset with most variables removed, or a selection of trial data which has undergone de-identification / anonymisation, and ceases to be personal data at the point of disclosure so the DPA does not apply. [2]• QMUL have claimed that re-identification from the requested (pseudo)anonymised data is a significant risk. However, there is no obvious or plausible method for a member of the public to do this without additional data that is held securely at QMUL and highly unlikely ever to come into the possession of myself or other members of the public. According to the ICO's Knowledge Base on FOI Policy with reference to the Data Protection Act, the onus is on public authorities to explain how re-identification would occur. [3] Speculative assertions about alleged 'extremists' may reflect the potential existence of a 'motivated intruder', but if such people exist they are highly unlikely to succeed in re-identification and therefore such speculation is irrelevant. In a previous unrelated ICO ruling, the Commissioner attempted to play the role of 'motivated intruder' and was unsuccessful. [4] Any fair attempts to play the role of 'motivated intruder' for the purposes of assessing this FOI request would also fail. The selected data being requested was chosen so that the results could be calculated from the bare minimum of data required (except without the optional criteria for recovery from a clinical perspective, and with the addition of 6MWD data).

• It is also the responsibility of the public authority to establish how disclosure would lead to adverse consequences. QMUL have stated that disclosure without explicit consent is unfair and "very likely" to cause "great distress" to participants to their obvious detriment, with adverse consequences such as revealing that an individual suffers from a certain health condition, and therefore constitutes a probable actionable legal offense. These assertions appear to be based primarily on the assumption that the requested data is strictly personal data that can identity trial participants when disclosed. As the requested data would not plausibly lead to identification of any individuals, the given hypothetical examples of adverse consequences do not apply, and it remains unclear how disclosure would constitute a serious invasion of privacy causing considerable distress if no individuals can be identified. The fairness test can be satisfied by removing identifiable information about individuals and/or by anonymising the data, "for example, by removing the name but leaving the rest of the information". [5]

• Much of the requested data is already one step removed from the information directly provided by trial participants e.g. fatigue and physical function numerical scores are calculated from multiple answers to different questions on a paper questionnaire, the specific answers of which cannot be reliably extrapolated from the summed numerical scores. The requested data consists of either dichotomous or continuous values which are common and/or fluctuating (it is not comparable to genetic information or a National Insurance Number). The data is quantitative not qualitative; it is not for example the written accounts of personal opinions, identifiable contextual experiences about personal lives, or the handwriting of living individuals.

• QMUL stated that explicit consent will not be requested from trial participants for this particular FOI request. Assuming that such consent is actually necessary for the release of non-identifiable anonymised trial data (which according to multiple references no longer qualifies to be classified as personal data), the Ministry of Justice guidance on s.40 also points out that "a public authority should not be able to engineer a situation in which data cannot be disclosed by failing to notify the data subjects". [5]

• QMUL stated that "Principle 2 of the Data Protection Act 1998 also does not allow data controllers to process personal data for further incompatible purposes." However, other public authorities tried to use this argument to refuse the disclosure of anonymised data and failed, because anonymisation and/or redaction did not count as a form of processing. [6]

• The GMC's guidance on confidentiality and MRC's guidance on data sharing, cited by QMUL, did not appear to prohibit the disclosure of non-identifiable anonymised data to members of the public. Obviously this does not mean unrestricted access to all data collected, but it certainly opens up the possibility of releasing selected non-identifiable anonymised data.

• The implications of anonymisation on confidentiality is somewhat less clear, but the s.41 exemption can only be applied if there is a good chance of a successful actionable breach of confidence, [7] which QMUL believes is the case. However, at least 2 expert commentaries suggest that anonymisation of confidential data can replace the need for consent, and can change the nature of the data so that in most contexts it is no longer 'personal data' and thus not subject to the legal duties of data protection. [8][9] It it also appears that the public interest can override the requirement for confidentiality. [10][11]

• The public interest strongly favours disclosure, but the argument is complex and involves specific details about the trial which cannot be easily summarised into a paragraph. Therefore I will add an additional annotation below describing the public interest argument in about 2800 words and providing appropriate references. Patients and clinical commissioners have a right to accurate information about treatments promoted to them as rehabilitative or potentially curative, but it can be demonstrated that the (apparently post hoc and possibly unapproved) redefinitions of improvement and recovery in the PACE trial were too lax (e.g. recovery thresholds overlapping with the trial eligibility criteria for severe chronic disabling fatigue and not guaranteeing no longer having CFS), that these outcomes were inaccurately presented as based on strict or conservative thresholds, and that the most controversial change to the physical function criteria was erroneously based on a misinterpretation of summary statistics from a population study. The FOIA appears to be most plausible method for finding out the results as promised in the original stricter PACE trial protocol. It is doubtful whether disclosure would actually deter future research. Conversely, it could be counter-argued that research candidates may feel discouraged from participating in controversial research topics if previous trials have involved major, questionable, and possibly unapproved, deviations from the pre-approved original protocol.

18 June 2014Reasons why the public interest strongly favours disclosure of the requested data:(FOI 2014/F73) 18th June 2014

Assertions about complete recovery and/or functional remission from any chronic debilitating illness with a poor prognosis that is regarded as difficult to treat should be taken seriously and be based on reasonably stringent definitions. However, a recent 2014 systematic review of studies on recovery from CFS (including the PACE trial) concluded that in general what the literature defined as 'recovery' is better described as modest clinical improvement only. There was no guarantee of 'recovery' per se, as classification was based on limited assessments, less than a full restoration of health, and self-reports lacking objective measures in function which when used in behavioural intervention studies suggested no changes (prompting the authors to conclude that these therapies for CFS were not rehabilitative as often claimed). [1] An earlier 2012 systematic review concluded that a "comprehensive rehabilitation programme only rarely results in full recovery". [2]

The PACE trial has been repeatedly presented as offering 'definitive' answers on the controversial issue of 'rehabilitative' treatments for CFS (e.g. in the official website FAQ, [3] in the trial statistical analysis plan, [4] by the Science Media Centre, [5] and on ABC radio [6]). The published definition of recovery/remission was presented by the principal investigators White et al. as 'comprehensive and conservative' and purported to use stricter thresholds than a previous study on recovery from CFS by Knoop et al. published in 2007. [7] However, multiple significant issues have been identified with the recovery criteria which strongly challenge or contradict these presentations and have not been adequately addressed by the authors. [1,8,9] Disclosure of the requested data will greatly help the resolution of these issues.

The thresholds used for the 'normal range' score of fatigue and physical function inappropriately overlapped with the trial eligibility criteria for 'severe fatigue' and 'significant disability'. The recovery definition allowed participants to be classified as 'recovered' without reporting clinically significant improvements to fatigue and physical function, as such improvements were not required and allowed a 5 point decline in physical function. No longer meeting Oxford criteria for CFS in the trial did not necessarily mean no longer meeting Oxford criteria or suffering from CFS in the clinic, because additional criteria for fatigue and physical function were required, and participants were classified as 'no longer meeting Oxford criteria' if they failed to meet a single one of these thresholds e.g. moving from a score of 65 to 70 points in physical function but remaining unwell. 11% of excluded candidates failed to meet these additional criteria despite otherwise meeting Oxford criteria, which itself also requires fatigue to be the only principal symptom (which is not a requirement of any other CFS case definition. [10] and 80% of candidates who were definitely or provisionally diagnosed with CFS before the trial were excluded from participation, with the most common reason being not meeting Oxford criteria for CFS).Improvement on the clinical global impression scale does not guarantee a recovery from CFS or any improvement in the primary outcome measures of fatigue and physical function. The optional requirements of not meeting CDC criteria for CFS or London criteria for ME were superfluous because these were not an entry requirement, tend to be more difficult to meet than the Oxfordcriteria in the first place, and were not applied properly in the trial. [7,11]

The relevant trial oversight bodies approved the original 2007 protocol published in BioMed Central, which included a much more stringent definition of clinically significant improvement ('positive outcome') and complete 'recovery'. [12] According to BioMed Central, "publishing study protocols will help to improve the standard of medical research by ... enabling readers to compare what was originally intended with what was actually done, thus preventing both 'data dredging' and post-hoc revisions of study aims". [13] The purpose of pre-publishing a protocol is to avoid accusations of cherry picking the results, but when the protocol is ignored this clearly cannot be guaranteed. The thresholds for clinical improvement on an individual patient level for the primary measures of fatigue and physical function were abandoned and replaced with weaker thresholds which have been criticized forbeing minimal. [14,15] Similarly, all components of the recovery definition were significantly modified in a manner which made them substantially less stringent and easier to qualify. Of particular note, the threshold for normal physical function was dropped from 85 to 60 out of 100 points, a score low enough that 13% of participants were already within the 'normal range' at baseline despite meeting trial eligibility criteria for 'significant disability' (65 points or less). [16] In contrast, participants originally had to improve a minimum of 20 to 25 points to physical function to be classified as recovered. Other researchers of CBT for CFS have even classified a score of 60 to 70 points as indicative of 'severe' impairments in physical function. [17,18]

Professor White previously requested that the threshold for a 'positive outcome' in physical function (later abandoned) be raised from 70 to 75 points, because the entry criteria had been raised from 60 to 65 to increase recruitment, so a 10 point gap between entry criteria and 'positive outcome' scores was needed to avoid a 'trivial' difference. [19,20] Now there is a 5 point gap in the opposite direction, which cannot not be described as a strict or 'conservative' threshold. Although it has been argued that protocols can change in light of new information, it is unclear how any of these changes could "more accurately reflect recovery" as asserted in the paper by White et al. [7] Furthermore, as the changes to the definition of recovery published in 2013 appear to be largely based on controversial post hoc analyses conducted for a previous paper on the trial results published in 2011, [21] it is unclear whether these major deviations from the protocol were approved by the relevant trial oversight bodies, and this confusion surrounding the timing of changes has reached the level of parliamentary debate in the House of Lords. [22]

As a previous claim made in the Lancet paper about the normative dataset used from a population study had turned out to incorrect, [23] it seemed prudent to examine the justification behind the most controversial change to the recovery criteria. White et al. asserted that the change to the threshold of normal physical function was justified because a score of ≥85 "would mean that approximately half the general working age population would fall outside the normal range". [7] However this is incorrect, as independent analyses of the English normative dataset cited by White et al. revealed that over half score the maximum of 100 points. The median(IQR) score for the general working age population sample is 100(90-100) not about 85 as implied (which suggested an erroneous assumption that the mean and median were equivalent), and only about 18% of the general working age population sample had a score under 85. [24] The original threshold of >=85 points appears to be reasonable and appropriate, as it "represents the ability to carry out moderate activities, such as lifting a table, carrying purchases, or bowling, without limitations". [25] 92% of the healthy working age population score 85 points or more, and 61% score the maximum of 100 points. The mean(SD) and median(IQR) scores for this population are 95.0(10.2) and 100(95-100) respectively, with scores under 80 appearing to be extreme outliers when defined as more than 3 x IQR below the median. [24] It is highly unlikely that the PACE trial participants classified as 'recovered' have a similar distribution of scores compared to a healthy working age population.

White et al. stated that "we derived a mean (S.D.) score of 84 (24) for the whole sample, giving a normal range of 60 or above for physical function" and asserted that this sample was "demographically representative". [7] However, the 'whole sample' was a general population which included the elderly and chronically disabled, [26] with age and illness having a major impact on physical function scores in a way which decreases the mean and increases the standard deviation, therefore lowering the threshold of 'normal'. The mean(SD) age was 48.3(19.0) years, 32% were aged 60 years or more, and 22% reported chronic debilitating illnesses (many of which would have medically excluded candidates from participating in the PACE trial). [24][26] Whereas PACE trial participants had a mean(SD) age of about 38(12) years at baseline, only 3% were aged 60 years or more, [27] and were previously screened for common chronic debilitating illnesses in the population which would have excluded them from a CFS diagnosis.Although described as a 'conventional' method, [23] White et el. have applied a simple parametric statistical method to a dataset without any apparent consideration for what the authors of the cited paper (Bowling et al.) described as a heavily skewed distribution, [26] which was specifically warned against in a paper previously co-authored by Professor White [28] and has been described elsewhere as a "fundamental misuse of statistics". [29]Furthermore, the use of normative data from a general population sample with important demographic differences to PACE trial participants (age distribution and presence of common debilitating illnesses) has never been justified in any of the publicly available PACE trial literature. It is unclear why the authors did not stop and think twice before using a 'recovery' threshold that was unusually low and overlapped with their own trial criteria for 'significant disability'. A score of 60 points means reporting significant limitations in multiple domains (somewhere between minor limitations for 8/10 questions or major limitations in 4/10 questions), [30] which is unusual for healthy people of working age and an unsuitable threshold for a genuine recovery. White et al. [7] incorrectly claimed that their threshold was more conservative" i.e. stricter than the previous work of Knoop et al. [28] The latter paper actually used the same mean plus or minus 1 SD formula as PACE did (not mean plus or minus 2 SD as claimed by White et al.), and relied on a healthy population instead of a general population to calculate a higher threshold of 80 points in physical function as the normal threshold for recovered. Similarly, serious questions have also been raised about the suitability of the threshold for normal fatigue and the population used to derive it. [8,31-33]

In response to the paper on 'recovery', Dr Esther Crawley from the University of Bristol said that "Every patient with CFS/ME wants to know how likely they are to recover." [34] Yet, many patients were rather unsatisfied with the major deviations from the previously established protocol, questioned the 'normal range' in particular,and wanted to know the 'positive outcomes' and more importantly the recovery rates as previously defined more stringently. A collection of patient charities made a FOI request for this information in 2011, which included the results according to the original recovery criteria [35] but were refused on the grounds that this information was exempt under s.22 of the FOIA i.e. due for future publication. [36] A similar FOI request in 2012 was refused on the grounds that the information was not held in final form because the definition of recovery had changed with a pending paper and there was no intention on publishing the requested information in the future (the refusal notice also incorrectly claimed that some of the changes made the definition more stringent). [37] Another FOI request in 2013 was refused on the grounds that the raw data required to calculate these outcomes does exist but would require over 18 hours to do so. [38] Therefore, this FOI request is for selected raw data so that these calculations can be done without QMUL.

ME/CFS is regarded as a controversial subject, but this controversy is only further fuelled by the lack of transparency over trial results presented as 'definitive' and the failure to publish the measures specified in the original approved protocol. Given that the published recovery thresholds appear to be fundamentally based on previous post hoc analyses, coincide with less than expected clinical improvements, and are generally at or below the level of the trial entry criteria, it is difficult to believe that the accusations of cherry picking or intentionally misleading vulnerable patients and clinical commissioners (irrespective of whether it is true or not) will simply go away without the publication of these stricter outcomes. It is critical that sufficient data is placed in the public domain to allow patients and clinical commissioners to accurately assess recovery and the sensitivity to any particular threshold.

There have been recent calls for medical research to be more transparent and accessible and accountable, as per the AllTrials campaign (www.alltrials.net). Although this does not necessarily mean unrestricted public access to all the data of a trial, AllTrials calls for "All trials past and present should be registered, and the full methods and the results reported." The Wellcome Trust takes a step further and calls for the full release of all trial data. [39] The public interest in transparency around drug trials has been well established by the European Medicines Agency and the same principles should apply to psychotherapy and/or behavioural interventions. [40] The PACE trial was publicly funded research and the (anonymised) data should be openly available to the maximum practical extent. Answers to remaining questions in science are generally gained from further replication, but the PACE trial cost taxpayers £5m, and due to its high cost and large size, it is highly unlikely that another similar trial will be conducted anytime soon. Therefore, the collected data should be explored to the maximum extent possible. Without voluntary transparency, the task of finding out the results as promised in the original PACE trial protocol depends on members of the public, and the FOIA appears to be most plausible method for seeing this happen in the foreseeable future.

The ongoing confusion and controversy is adding to the suffering of patients, and getting to the bottom of this issue is important whatever the outcome may be. The results and interpretations do not just affect those who are curious about research, but have national and perhaps even global ramifications. Patients and clinical commissioners of this chronic debilitating illness have a right to accurate information about treatments which are promoted to them as rehabilitative and potentially curative. This is required for them to assess and give informed consent for treatments, or make informed decisions about health care. Lax definitions of recovery/remission and clinical improvement lead to unreasonable expectations from patients by those who provide their care. In a similar study known as the FINE trial [41] (which released the results according to its own published protocol and failed to show significant improvements with therapies similar to and sharing elements with CBT/GET tested in the PACE trial), some participants had doubts about the (overly optimistic) treatment rationales, and therapists reported becoming angry and blaming participants as "the bastards don't want to get better". [42]

It is doubtful whether disclosure would actually deter future research. Conversely, it could be counter-argued that research candidates may feel discouraged from participating in controversial research if previous trials have involved major, questionable, and possibly unapproved, deviations from the pre-approved original protocol which made it much easier for the tested therapies to appear successful, coincided with less impressive than expected results, and led to the results being exaggerated. For example, the published rates of trial participants within the 'normal range' for fatigue and physical function (which overlapped with trial eligibility criteria for severe chronic fatigue and significant disability) was presented in 2011 at a Lancet press conference with the principal investigators as returning back to normal, [43] and this was then widely misinterpreted as a complete recovery or cure in the national news media e.g. [44,45] and medical journals e.g. [46,47] The Lancet editorial which accompanied the 2011 paper on the PACE trial results inaccurately claimed that the 'normal range' was a strict criterion for recovery based on scores from healthy people, [48] but the Press Complaints Commission later ruled that this comment was misleading and breached Clause 1 (Accuracy) of the Code. [49] Such repeated misstatements of fact have negative implications for how patients are treated by doctors, how funding decisions are made, and for scientific accuracy concerning recovery from ME/CFS. A poll conducted on the ME Association website during March 2011 revealed that 89% of 751 respondents were significantly concerned that the PACE trial results would adversely affect treatment within the NHS. [50]

Unless the PACE group themselves promptly publish the original protocol-defined 'positive outcomes', the original protocol-defined 'recovery' rates, and summary statistics on those classified as recovered (both versions) compared with appropriate summary statistics of healthy populations with a similar age distribution as trial participants, then the disclosure of the requested data allowing others to do the necessary calculations is certainly in the public interest. Given that the lax definition of 'recovery' fundamentally depends on a threshold for 'normal' physical function which appears to be seriously flawed and inaccurately presented as strict or conservative, with the reason for abandoning the original protocol-defined threshold found to be erroneously based on a misinterpretation of summary statistics from a population study, the requested data will be important to help the public (patients, carers, research community, healthcare staff, et cetera) further assess the degree and nature of improvements in the PACE trial.Please help resolve this controversy once and for all by granting this FOI request.

• If there is any doubt about the ease of which some trial participants could be disqualified from meeting Oxford criteria at followup (for failing any additional ad hoc criteria bolted onto the Oxford criteria for the purposes of the trial), QMUL previously stated: "A score of 70 or more on the SF-36 sub-scale would mean that the participant did not meet Oxford criteria. Similarly having a score of 5 or less on the Chalder fatigue questionnaire would mean that the participant did not meet Oxford criteria." [1] This is not usually part of the Oxford criteria and means that no longer meeting Oxford criteria at followup in the trial could be achieved by borderline cases improving a single increment on either scale but who could still be significantly affected by CFS and still otherwise meet Oxford criteria outside the trial setting. In the original trial protocol, a fatigue score of 5/11 on the CFQ (bimodal scoring) and a score of 70/100 on the physical function sub-scale of the SF-36 were still both regarded as abnormal scores, and required a fatigue score of 3/11 and a physical function score of 85/100 to be classified as recovered. [2]

• Re: "11% of excluded candidates failed to meet these additional criteria despite otherwise meeting Oxford criteria". This was based on Figure 1 of the 2011 Lancet paper, [3] but it is not entirely clear how many excluded candidates failed to meet each stated reason for exclusion, as only one reason is given for each exclusion but it is plausible that excluded candidates failed more than one. Out of the 2517 candidates who were excluded (all of which had previously been definitely or provisionally diagnosed with CFS), 43% were excluded for not meeting Oxford criteria, 10% were excluded for scoring over 65/100 points in physical function, and 1% were excluded for scoring under 6/11 points in fatigue, suggesting that some excluded candidates still had CFS.

• A video has been made demonstrating how a trial participant could improve a single increment in fatigue, decline a single increment in physical function, report feeling significantly better e.g. due to pain medication, and then be classified as 'recovered' despite remaining significantly unwell with CFS. [4] Some participants would have to improve more to cross the thresholds, but it demonstrates a problem with the lax recovery criteria and that combining multiple recovery criteria does not necessary negate the weaknesses of each individual criteria. The definition of 'recovery' is simply too lax to justify the use of the word 'recovered', particularly without objective measures (which when used have generally shown a lack of clinically significant improvement).

• Re: "The thresholds for clinical improvements on an individual patient level for the primary measures of fatigue and physical function were abandoned and replaced with weaker thresholds...". To further clarify in context with the sentence which preceded it about BioMed Central's statement on post hoc revisions, the latter thresholds were the 'clinically useful difference' i.e. 2/33 points in fatigue (Likert scoring) and 8/100 points in physical function, which did not appear in the final version of the statistical analysis plan, [5] and were described as post hoc in the 2011 Lancet paper. [3] It is unclear when these were introduced and whether they were approved by the relevant trial oversight bodies (see below for why doubts have been raised).

• Re: "as the changes to the definition of recovery published in 2013 appear to be largely based on controversial post hoc analyses conducted for a previous paper on the trial results published in 2011". To further clarify, the methods and thresholds for the normal range for fatigue and physical function used in the revised definition of recovery did not appear in the final version of the statistical analysis plan [5] and are exactly the same as the post hoc analyses that were introduced during the peer review stage [6] of the fast tracked 2011 Lancet publication [3] (i.e. not introduced by the authors themselves). This is why doubts have been understandably raised over whether the changes to the recovery thresholds were approved by the relevant trial oversight bodies and whether the recovery definition was revised after rather than before these post hoc analyses were conducted, which would contradict the published impression that the changes were made to the recovery criteria before analysing any data. [7,8]

If you think the P2P panel is the most hare-brained scheme you've ever heard of, you are probably right.

The NIH somehow came up with the wacky idea that the best people to decide how to define, treat, and diagnose a complex illness are not medical experts, nor indeed doctors, but a motley assembly of ethicists, lawyers, statisticians, and other unrelated professionals who have no knowledge at all of the illness whose financial fate they hold in their hands.

Now, in an effort to appear fair-minded, the P2P has "opened" its doors to public input for its literature search. I say "opened" because some of the restrictions placed on what constitutes acceptable literature are almost as ludicrous as the panel itself.

Nonetheless, it is good idea to submit studies that demonstrate the various physiological abnormalities found in ME/CFS patients. As far as diagnosis is concerned, the most appropriate studies would be those documenting immune, neurological, and mitochondrial impairments, as well as exercise intolerance, as these can be used to aid in diagnosis.

I am a firm believer that whenever someone in an official capacity invites our input, we should input like mad.The deadline for submitting research is July 17th.**************************************************************************

SUMMARY: The Agency for Healthcare Research and Quality (AHRQ) is seeking scientific information submissions from the public. Scientific information is being solicited to inform our review of Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), which is currently being conducted by the Evidence-based Practice Centers for the AHRQ Effective Health Care Program. Access to published and unpublished pertinent scientific information will improve the quality of this review. AHRQ is conducting this systematic review pursuant to Section 1013 of the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, Public Law 108-173, and Section 902(a) of the Public Health Service Act, 42 U.S.C. 299a(a).

SUPPLEMENTARY INFORMATION: The Agency for Healthcare Research and Quality has commissioned the Effective Health Care (EHC) Program Evidence-based Practice Centers to complete a review of the evidence for Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

The EHC Program is dedicated to identifying as many studies as possible that are relevant to the questions for each of its reviews.

In order to do so, we are supplementing the usual manual and electronic database searches of the literature by requesting information from the public (e.g., details of studies conducted). We are looking for studies that report on Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), including those that describe adverse events.

The entire research protocol, including the key questions, is also available online at:

This notice is to notify the public that the EHC program would find the following information on Diagnosis and Treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

- A list of completed studies your company has sponsored for this indication. In the list, indicate whether results are available on [[Page 34539]] ClinicalTrials.gov along with the ClinicalTrials.gov trial number.

- For completed studies that do not have results on ClinicalTrials.gov, a summary, including the following elements: Study number, study period, design, methodology, indication and diagnosis, proper use instructions, inclusion and exclusion criteria, primary and secondary outcomes, baseline characteristics, number of patients screened/eligible/enrolled/lost to follow-up/withdrawn/analyzed, effectiveness/efficacy, and safety results.

- A list of ongoing studies your company has sponsored for this indication. In the list, please provide the ClinicalTrials.gov trial number or, if the trial is not registered, the protocol for the study including a study number, the study period, design, methodology, indication and diagnosis, proper use instructions, inclusion and exclusion criteria, and primary and secondary outcomes.

- Description of whether the above studies constitute ALL Phase IIand above clinical trials sponsored by your company for this indication and an index outlining the relevant information in each submitted file.

Your contribution is very beneficial to the Program. The contents of all submissions will be made available to the public upon request.

Materials submitted must be publicly available or can be made public.

Materials that are considered confidential; marketing materials; study types not included in the review; or information on indications not included in the review cannot be used by the Effective Health Care Program. This is a voluntary request for information, and all costs for complying with this request must be borne by the submitter.

1. What methods are available to clinicians to diagnose ME/CFS and how do the use of these methods vary by patient subgroups?A. What are widely accepted diagnostic methods and what conditions are required to be ruled out or excluded before assigning a diagnosis of ME/CFS?B. What is the accuracy and concordance of diagnostic methods?C. What harms are associated with diagnosing ME/CFS?2. What are the (a) benefits and (b) harms of therapeutic interventions for patients with ME/CFS and how do they vary by patient subgroups?A. What are the characteristics of responders and non-responders to interventions?

Oli Smith, now 19, was a high-flying student at his local high school in the Black Isle before he developed ME, or chronic fatigue syndrome, in 2008.

He missed months of schooling and his parents, Bev and Bryan, begged for help. However, despite the named person scheme, the family insist they were treated with contempt.

At one stage, after Oli used a swearword to describe his deputy head teacher in a post on his blog, his state guardian supported a decision that he should be reported to the police.

The scary thing is to think that if everything put through now had been in place when I was at school, I’ve no idea where I would be – I probably would not have been allowed to stay with my family

His parents were stunned when two officers arrived to interview Oli at home in Fortrose during his English Standard Grade exam.

The proposal to introduce a named person for every under-18 in the country was introduced as a pilot in the Highlands five years ago and has since been lauded as a “great success”.

However, campaigners say this does not take into account a number of long-running complaints from families who say the policy is intrusive.

His story emerged after the Young ME Sufferers Trust announced on Friday it would be joining a legal bid to halt the Scottish Government’s state guardian plans.

The charity described the policy, now law thanks to the Children and Young People (Scotland) Act, as an “oppressive, unwarranted and illegal intrusion into family life”.

Last night, Oli – now studying for a computer games degree at Abertay University – said: “It is something that is taking the control of their own lives away from young people.

“The named person is supposed to put the child first but my views were never listened to at any stage.”

He added: “Without scaremongering, I’m a science fiction fan and this policy seems like it is turning Scotland into a dystopian vision of the future.

“The scary thing is to think that if everything put through now had been in place when I was at school, I’ve no idea where I would be – I probably would not have been allowed to stay with my family.

“We were labelled all manner of things and I daren’t even think where I might have ended up if my named person had been backed by legal statute as they are now.”

When Oli’s illness began, his parents say that his guidance teacher accused him of “playing up” and threatened to call at their house every morning to get him up and into school.

At the end of the year, his parents discovered the youngster had attended sick bay 17 times in two months without them being informed.

Oli repeated his S3 year and was officially diagnosed with ME, yet his parents claim that teachers would still make “openly derogatory” comments about his non-attendance.

After several more years of difficulties, Oli managed to sit five Standard grade exams with the help of a private tutor and home schooling.

However, he was left very anxious about attending school and having any contact with some members of staff.

His parents say they had requested several times for Oli’s named person to step in and help resolve the problems, but they were ignored.

With his exams coming up and suffering from “uncertainty and confusion”, he made his regrettable online comment about the school’s deputy head teacher.

She was monitoring his blog and – with the backing of Oli’s named person but without informing the family – made a complaint to the police. Mrs Smith said the officers were apologetic when they arrived, adding: “They took no action apart from a friendly chat but the visit was devastating for Oli and highly detrimental to his exams”.

Oli was then permanently excluded and – although this punishment was overturned – he moved to a new school 30 miles away for his final two years with his parents renting a flat for him nearby.

However, the council did not remove the exclusion from his records as agreed and although the situation improved, Oli suffered a number of relapses and endured a “chaotic, stressful” end to his schooling.

Mrs Smith said: “The Scottish Government say the named person scheme worked so well in the Highlands but we know it didn’t work for us. It wasn’t just falling slightly short, it just wasn’t happening at all. The council were happy to ignore the groundswell and say how well it was going, even though the feedback was gathered from a very small group of families.

“Barnardo’s also said it had been a success in the Highlands even though its report was based only on the experience of looked-after [children directly or indirectly under the care of the local authority] children.The family had hoped to put the experience behind them but with the named person policy about to be rolled out across Scotland and backed up by law, they are preparing to join the growing campaign against it.However, for Oli, although he still suffers from fatigue, he is finding out that life as an adult with no state interference is a breath of fresh air.He said: “Where I am now is entirely different to where I was while at school, I feel I am able to live my own life.”

A Highland Council spokeswoman said: “The council takes a firm approach to abusive or threatening comments on social media.”

The following announcement comes from the FDA Treatment Team, a group of people dedicated to securing FDA approval for Ampligen.

The team has drafted a letter requesting a congressional hearing on Ampligen. You can support their effort by sending your own letter (see template below).

The team has provided email addresses on their template letter. In addition, I recommend you send the letter to your own representatives as well via their web forms. Representatives always pay attention to letters sent by their constituents. You can find your representatives HERE simply by typing in your zip code...................................................................................................

New Opportunities to Create FDA Action on ME/CFS Treatments

Currently, Congressmen Fred Upton (R-MI) and Diana DeGette (D-CO) have spearheaded a bipartisan initiative called "21st Century Cures" to increase the pace of medical breakthroughs. This initiative gives us fertile ground to press Congress and the FDA to provide an environment that attracts drug companies to ME/CFS research and for the FDA to give conditional approval of Ampligen. Remember, if we get one drug across the line, many more will follow.

We are asking you to help us continue to push the FDA to foster and approve treatments for ME/CFS. It is important that ME/CFS stay high on the FDA's agenda. Please cut and paste the following message and send it to the email addresses below.~From The FDA Treatment TeamCort Johnson, Bob Miller, Billie Moore, Pat LaRosa, Dr. Janet Smith, Anita Patton, and Lori Chapo-Kroger..................................

Subject line:FDA fails to approve drug for ME/CFS - Time for a congressional hearing

In the body of the email:

Recently, Congressmen Fred Upton (R-MI) and Diana DeGette (D-CO) spearheaded a bipartisan initiative called "21st Century Cures" to increase the pace of medical breakthroughs. This initiative provides opportunities to help speed approval for treatments that affect underserved populations - such as those who are severely ill with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome).

To date, the FDA has failed to approve a drug considered safe for ME/CFS, leaving chronically ill patients to take untested, off-label medications. ME/CFS costs the United States economy approximately $20 billion annually and affects one million Americans. It has left many families in ruins.

The FDA says it will approve drugs with serious adverse side effects that they believe are effective for ME/CFS, but they won't approve Ampligen, a drug that they acknowledge is safe.

Where is the data on efficacy and safety of the drugs currently being used off-label to treat ME/CFS?

ME/CFS Expert Dr. Charles Lapp, who has treated thousands of ME/CFS patients and has used Ampligen for more than 25 years, said, "Even if Ampligen doesn't improve a patient, it does no harm."

The experts have said it works, and the FDA Advisory Committee has said it's clear that patients are experiencing benefit. More than 700 patients provided testimony at the FDA Advisory Meeting in December 2012 requesting approval of Ampligen, and more than 4,000 signed a petition after FDA denied the approval in February 2013.

In April of 2013 - four months after the FDA denied approval for Ampligen - the FDA admitted they did not have a complete understanding of ME/CFS. We believe that if the FDA had understood the unique needs of ME/CFS patients prior to the Ampligen approval hearing, the drug would have received conditional approval, leading to a functional improvement in many severely ill patients.

The FDA is to be commended for acknowledging the seriousness of ME/CFS. However, more needs to be done. The FDA needs to recognize the special circumstances and desperation of the ME/CFS community and act accordingly by assisting drug companies in bringing their products to market.

A group of patient advocates has demanded a congressional hearing, and I agree. A congressional hearing is needed. The FDA must live up to its commitment and help those with chronic illnesses. We have a right to treatment; our voices and our experts need to be heard.

Action for ME published two reports during ME Awareness Week (May 11 to 17) 2014. The survey was based on responses from more than 2,000 Action for ME members in 2014.

According to the website:"Revealing the daily challenges faced by those affected by M.E./CFS in the UK, M.E. Time to Deliver details the impact of M.E./CFS symptoms, highlighting in particular what life is like for those who are more severely affected, including primary and secondary healthcare for people with M.E./CFS, their experience of welfare benefits, social care, employment and education."You can read the executive summary or read the full M.E. Time to Deliver.

The study did manage to accomplish its goal; it showed how inadequate care is for people with ME in the UK. It was not at all surprising that the majority of participants reported GPs who were uninformed about the illness, poor experiences in clinics, lack of specialty care, no follow-up after medical visits, delayed or reduced welfare benefits, and so on. These experiences are nearly universal.

What was interesting about the survey were the conflicting statistics.

The results of the survey showed that:

A third of people with M.E./CFS had tried cognitive behaviour therapy; half said they found it helpful or very helpful, while around one in 10 said it made them a bit or much worse.

Around one in five people with M.E/CFS had tried graded exercise therapy; a third said they found it helpful or very helpful, while nearly half said it made them a bit or much worse.

These positive results would seem to indicate that CBT, and GET are successful therapies for ME/CFS, at least for a subgroup. Of the roughly 700 people who had tried CBT, 350 said it was helpful. Yet, only 200 people were working normal hours. "Helpfulness" does not, in this case, mean a return of function. So, what does it mean? The survey didn't ask, so we can't know

Of the 400 people who had tried GET, 200 said it made them worse, while 133 said it had been helpful. But, once again, what is meant by "worse" and "helpful?" Does "worse" mean lying flat on one's back for long periods of time? Does "helpful" mean a lift of the spirits, even while one remains flat on one's back? To gain any sense of what these terms mean, they need to be clearly defined in terms of function, not feeling.

Self-rated severity of illness also told an interesting story.

36% of the survey respondents said they were mildly ill, and less than one in 10 people said they were in full-time paid work, education or training, with only 14% in part-time paid work, education or training.

Around 90% of people with ME/CFS had either stopped or reduced paid work and social contact, while half had reduced or lost capacity to drive and a quarter were no longer able to leave their home independently.

If one were to compare numbers, roughly 700 people said they were mildly ill, yet fewer than 200 people were still working normal hours. That means that the majority of mildly ill patients had stopped working. If an illness is serious enough to prevent a person from working or attending school, it cannot, by definition, be mild.

When designing a broad survey of this nature, it is important to ask people questions that apply to how they are functioning - rather than how they are feeling - for the simple reason that most patients who have had ME/CFS for a long time have adjusted to it. If you had been bedridden for years, let's say, but can now drive, do light housework or some shopping, and talk on the phone or visit with friends for an hour or two, you might consider yourself to be mildly ill. Yet, you cannot work, go to school, attend an evening event, stand up and chat at a party, or do anything that might strain your system. Given those restrictions, no healthy person would define that lifestyle as being mildly ill.

Surveys that do not provide for the disparity between how patients interpret the words "mild," "moderate," "severe," "helpful," "worse" and how these words are interpreted by social programs, physicians, and government agencies do not, in the end, serve any practical purpose.

With the amount of attention that has been garnered by the IOM contract, a second federal initiative, the Pathways to Prevention, or P2P Workshop, has gone almost unnoticed. Yet, of the two initiatives. the P2P Workshop has the most potential to cause serious harm to the patient community.

The P2P process was begun in June 2012 when the Trans-NIH ME/CFS Research Working Group and Office of Research on Women's Health (ORWH) began formulating a proposal. Part of that proposal was a workshop, two days of presentations on which the panel would base its recommendations for a research case definition. The first working group meeting to plan the workshop was held in January 2014. The tentative date for the workshop is December 2014.

Why the P2P is a potential time bomb

The P2P Workshop was convened by the NIH for the express purpose of "identifing research gaps and methodological scientific weaknesses in a scientific area, to suggest research needs, and to move the field forward through an unbiased and evidence-based assessment" (Susan Maier, IOM public meeting January 2014). This differs from the goal of the IOM, which is to devise a new clinical case definition.

But, since the January 2014 IOM meeting, the purpose of the P2P has been broadened to include a review of all case definitions, diagnosis, treatment, patient subgroups, research, and anything else that suits their fancy. The reason this is a potential time bomb is that once the P2P submits its "everything but the kitchen sink" report, the NIH will disseminate it far and wide. It will become the basis upon which research grants are evaluated, and, eventually, upon which pharmaceutical companies base their clinical trials.

A sloppy or inaccurate report - let's say one written by people with no knowledge of the illness and who have only 24 hours to write up their findings - could be the downfall of any meaningful ME/CFS research in the future.

Why the P2P doesn't seem to know what it is doingThe P2P panel consists entirely of people who have no experience with ME/CFS. Panel members don't even need to be doctors. According to Susan Maier, Deputy Director of the ORWH (this is the department responsible for ME/CFS), panelists can be anybody - methodologists, ethicists, attorneys - as long as they have no connection to ME/CFS. The panel will make its recommendations after hearing two days of 20-minute presentations made by people who supposedly have expertise in ME/CFS.

According to Dr. Maier's presentation at the IOM meeting last January, the questions the workshop was supposed to have addressed were:

How do ME and CFS differ?

What tools will allow us to define subsets across the entire subset of CFS?

What are the characteristics of patients who respond to specific treatments across the spectrum of CFS?

What does research on ME/CFS tell us about clinical diagnosis of ME/CFS?

Have previous research findings shaped current clinical practice or are research and clinical practice completely separate?

These questions were supposed to be "refined" through a systematic review. However, the protocol for the systematic review asks a set of questions that are focused on clinical definitions and therapies, not research. Here are the key questions of the review:1. What methods are available to clinicians to diagnose ME/CFS and how do the use of these methods vary by patient subgroups?a. What are widely accepted diagnostic methods and what conditions are required to be ruled out or excluded before assigning a diagnosis of ME/CFS ?b. What is the accuracy and concordance of diagnostic methods?c. What harms are associated with diagnosing ME/CFS?2. What are the (a) benefits and (b) harms of therapeutic interventions for patients with ME/CFS and how do they vary by patient subgroups?c. What are the characteristics of responders and non-responders to interventions?

To make the matter even more confusing, the draft agenda - obtained by Jennie Spotila through the Freedom of Information Act - appears to be headed in yet another direction.

The first item on the agenda is "overwhelming fatigue or malaise as a public health problem." This not only represents a radical departure from "How do ME and CFS differ?" it seems to be omitting the very illness(es) the P2P is supposed to be studying.

The agenda also has been expanded to include 20-minute presentations on treatment, specifically:

Cognitive Behavioral Therapy

Graded Exercise Programs

Symptom-based Medication Management

Harms

Patient-Centered Outcomes

Quality of Life

Looking at the list, it is clear that the panel is considering the idea that ME/CFS may be a form of mental illness. (Two of these are modalities suited to depression, i.e. CBT, GET). The rather enigmatic category of "harms" is puzzling. By "harms" the panel is referring to the psychological harm of having the label of ME/CFS as a diagnosis, but they also mean possible risks from tests (e.g. the 2-day CPET). In any case, it is difficult to see how these questions can further scientific research into ME/CFS, which is what Susan Maier originally claimed the P2P would accomplish.

Pulling the plug on the P2P

If you are having a hard time following this continually shifting kaleidoscope of what the P2P is supposed to be doing, so is everybody else, which is why Jennie Spotila and Mary Dimmock sent a letter to Dr. Francis Collins, Director of NIH, requesting that he cancel the P2P Workshop on ME/CFS and reexamine how to best collaborate with the ME/CFS research and clinical community.

The letter cites five reasons why the P2P Workshop should be canceled:

The Workshop is unnecessary and redundant of other efforts on research and case definition.

The Workshop is examining the problem of medically unexplained fatigue, not ME/CFS.

NIH has not engaged or involved stakeholders in a substantive way.

The Workshop is inappropriate for this disease, particularly because the decision makers are non-ME/CFS experts.

The goal of the Workshop is unclear because HHS has made numerous contradictory statements about its purpose.

With attachments and supporting documentation, the package came to 38 pages.

What we can do

Even if you don't think sending a letter to Dr. Collins will result in a cancellation of the P2P Workshop, it is crucial that the ME/CFS community voice its concerns. In Mary Dimmock's words:"We need a complete overhaul of public policy that breaks the cycle of bad science that has captured this disease. To get that change, we are going to need to demand it and not just live with what we can get. You've all lost too much of your lives to accept any less."We gain nothing from silence.Fax Dr. Collins at 301-402-2700 or email him at collinsf@mail.nih.govYou can use the template below............................................Dear Dr. Collins:I am writing to request that you cancel the P2P Workshop on ME/CFS. I believe that the P2P Workshop will not advance us towards the much needed ME/CFS research case definition or strategy, for the following reasons:

ME/CFS experts have already adopted the Canadian Case Definition for research. No new definition is needed.

The Workshop is examining the wrong illness. They are examining "medically unexplained fatigue," not ME/CFS.

NIH has not engaged or involved stakeholders in a substantive way.

The Workshop panel consists of non-ME/CFS experts.

HHS has made numerous contradictory statements about the purpose of the Workshop, so its goal is unclear.

I understand that you have recently been provided with extensive documentation from Jennifer Spotila and Mary Dimmock concerning these five points. Careful consideration of the above issues raises legitimate concerns about whether the P2P Workshop will produce good science and sound recommendations.I hope you will give my concerns a fair hearing, and that you will cancel the P2P Workshop.Sincerely,[Your name]

I had the rare pleasure of interviewing Dr. Judy Mikovits at the IACFS/ME conference in San Francisco last March. Dr. Mikovits is best known for her involvement with XMRV research.

Dr. Mikovits is a cellular and molecular biologist with over 30 years of scientific expertise. She has directed programs on HIV, cancer, epigenetics, and neuroimmune disease, with a focus on development of novel drug and diagnostic technologies. Dr. Mikovits holds a PhD in Biochemistry and Molecular Biology from George Washington University. Her dissertation was on HIV latency and mechanisms of immune activation in monocytes. Dr. Mikovits was a Postdoctoral Scholar in Molecular Virology at the Laboratory of Genomic Diversity, National Cancer Institute under Dr. David Derse. Over the past 26 years, she has published 51 scientific papers in peer-reviewed journals.

The riveting story of XMRV, and the subsequent scandal which left her career in ruins, is told in Dr. Mikovits' forthcoming book, Plague: One Scientist’s Intrepid Search for the Truth about Human Retroviruses and Chronic Fatigue Syndrome, Autism, and Other Diseases. It was a journey that took Dr. Mikovits through the process of scientific research, the thrill of discovery, and ultimately to the high-level corruption which eventually led to her arrest, and the conviction and sentencing to federal prison of her employer, Harvey Whittemore, for federal crimes that, in the words of Nevada's highest court, reflected badly on his “honesty, trustworthiness or fitness as a lawyer.”

In spite of the notoriety surrounding XMRV, Dr. Mikovits remains committed to helping people who suffer from ME/CFS and is determined to discover its cause. “To me,” she says, “it's the patients that matter.”

Dr. Mikovits continues to work on neuroimmune disease and cancer at MAR consulting, an endeavor she shares with Dr. Francis W. Ruscetti. http://www.marconsultinginc.com/home.html

Plague will be released on July 1. You can pre-order it now from Amazon at a guaranteed 30% discount. (Note: This discount will not be available after the release date.) Order here.

That's a good story. In late November of 2005, I met Kristin Loomis, the head of the HHV6 Foundation. Kristin visited my lab and got excited. Her daughter, who was very sick, had been diagnosed with CFS, but Kristin thought she had HHV6. What I saw in Kristin Loomis' daughter was an astounding loss of intelligence and cognitive function, which was striking in such a young person.

At the time, my company, EpiGenX Pharmaceuticals, was being sold, and I didn't have much to do. So, I agreed to work for Kristin as a consultant on HHV6, to put the research together. In 2006, Kristin sent me to the HHV6 meeting in Barcelona where I met Dan Peterson. He gave a very compelling talk. His data showed clonal rearrangement of gamma delta T cells; you don't get clonalities like that unless you've got a frank cancer. He said, “I don't see where all this cancer is coming from. I don't know what it means. If anybody can help me, see me after the talk.” I took one look at the slide, and I could not get to him fast enough. He invited me to Reno, where I met the Whittemores.

So, you got hooked because you saw something very strange.

It was the mantle cell lymphoma that was the red flag. Dan Peterson had five patients with mantle cell leukemia in a group of 100, which appeared to be a cluster. The way I've been trained, I look at cancers and I look at clusters. So, I thought, “There's something going on,” because mantle cell lymphoma is incredibly rare.

Did you know anything about ME/CFS before you met Dr. Peterson?

At that time, CFS was really nothing to me, because when I looked at the literature I thought, “Fine, they've got an NK problem.” That makes sense, because NK [natural killer] cells only do two things, they recognize viruses and they recognize tumor cells. So, if you can't clear viruses, you're going to have NK cell disturbances. After I met Dan, I purposely didn't read the research, because I wanted to discover what was going on without being influenced by previous research.

The one exception I made was a paper by Paul Levine. His paper was about families that had children who had cancer and CFS. NK function was lowest in the children with cancer. But CFS patients had only slightly more NK function. I carried that paper in my backpack wondering why.

How did you begin working with him?

To me, it's the patients that matter. I basically saw a sick patient population – and they were so sick. These were young people, the promise of the country. Something had to account for it.

From the day I went into the field, I saw a crippled immune system. That's what Dan Peterson showed me – a crippled immune system.

So, all that summer I worked with Dan Peterson. We took multiple samples of the most severely ill patients. We took samples every six weeks, so we developed a very good database. It's important to have a database like the one we were creating, because if you do a snapshot of an immune profile, you capture only one day. You might miss something. The virus(es) may be latent, so you have to take repeated samples over several time points, months apart.

That was how we found XMRV. We didn't see it in of 67/101 samples, we saw it in 67/101 patients. And we had multiple samples from every patient taken over a two-year period. The reason we needed so many samples was that there could be DNA silencing of the virus by methylation, the very mechanism that was the basis of my startup, EpiGenX.

For me it made perfect sense based on my decades-long work on HIV and HTLV-1. I had published a paper on how methylation of immune modulators in HIV-infected people silenced the virus, and now I was finding something similar with CFS. [DNA methylation suppresses the expression of endogenous retroviral genes. It plays a crucial role in the development of nearly all cancers.]

Do you still believe a retrovirus causes ME/CFS?

We never said cause. It was the adversaries that said cause. What we said was that there was an association. Everyone wanted to make this virus like HIV, but it's not like HIV. It's not crippling the immune system so badly that people are dying quickly. And it's not a large visible cell component that is being crippled, like the CD4 T cell.

If you want to find a retrovirus you've got to grow it in a dividing cell, because it needs cellular genes to multiply, and it's not easy to find. So we used the classic techniques. And the association with XMRV was very strong. We had a transmissible retrovirus from the third family of retroviruses. It was first associated with a cancer, and now we found it was associated with a neurological disease, just like HTLV-1.

If XMRV was a lab artifact, why wasn't it in all the samples – those from healthy people as well as from those who were sick?

Only the samples we sent to Silverman's lab got contaminated, but these were all samples from patients. So samples from healthy controls didn't get contaminated.

In our paper, the hypothesis was that we would find a retrovirus. We did experiments in 2008 that did not quite match Silverman's XMRV plasmid sequence. Because we couldn't make the match with Silverman's XMRV, we modified the parameters. We changed the PCR reaction to capture everything that wasn't an exact match. This is what we call “wobble” or “variation.” Max Post was the person who captured the variation in our samples.

When we pulled those pieces out and sequenced them, we were getting similar, but not exact matches with Silverman's XMRV.

Silverman asked for 30 samples, which we provided. But he wouldn't do his work blinded, so he knew they were from patients. Our work was blinded, but my notebooks were the only way you could figure out which sample was associated with which patient. Silverman provided his own controls.

So, after three tries Silverman still couldn't get a full-length sequence of the virus we were looking at. That meant that what we sent him simply was not XMRV Silverman. He said in March 2009, “Let me try again.” We replied, “No, there's too big a chance of contamination.” But Lombardi cultured the virus and sent Silverman the samples anyhow without telling me. That was a mistake. When Silverman sequenced those samples – which were not blinded – in his laboratory, they got contaminated. Silverman had lots of plasmid in his laboratory, as he had been doing all the sequencing. He notified us in July of 2011 that our samples were contaminated with his VP62 plasmid.

But even if what we found wasn't Silverman XMRV, it was still associated with two diseases – the lymphoma in Dan’s patients and CFS. It could have been a family of viruses, or a different strain. For example, there are five strains of HTLV, and only one is pathogenic. What we found could have been just one in a family of retroviruses.

A good example of this problem is Dr. Lipkin’s research. Dr Lipkin says he has found evidence of retroviruses in Montoya’s samples of ME/CFS patients, but he claims this probably doesn’t mean anything because he also found them in the controls. But what if the controls have a non-pathogenic strain? No one has a detailed sequence that would enable anyone to know those answers. And only 5% of the people infected with HTLV-1 ever get disease.

After 40 years we still don’t know the exact mechanisms of how HTLV-1 or HIV cause disease and why the other very closely related strains do not. The point is that healthy people do not express human retroviruses endogenous or otherwise! Of course there are missing links, but to abandon a line of research that could help millions of people is just bad science.

So, if it wasn't Silverman's XMRV plasmid, what virus did you find in Dan Peterson's patients?

We isolated a gammaretrovirus from at least one person. And I believe beyond a shadow of a doubt that it was a new gammaretrovirus that could infect humans. The way we found it was by using a reagent called a 7C10 monoclonal antibody, which was an antibody to murine gammaretroviruses. That antibody recognizes all known murine gammaretroviruses.

The problem was that every time we put our sequence in the database it came up with XMRV, because that's all there was. There was nothing else to compare it to. When De Freitas did her work in 1990 she had the same problem. She found HTLV-1 and HTLV-2-like virus because, back then, that's all there was in the database.

So, every time we put a sequence in the database, it came up with XMRV because there was nothing else to check it against. But you have to remember that XMRV isn't a single virus, it's a family of viruses. And there may be many other retroviruses that are similar to it that may be pathogenic to humans. We just don't have a way of identifying them through a database right now.

If you found a new retrovirus, why was the paper you published in Science retracted?

The paper should not have been fully retracted. It should have been partially retracted. The only reason the paper was fully retracted was because I was jailed and had no access to our data.

One of the things that was so wrong about what happened is that they threw out all my research. They destroyed it all. And this is the saddest part; we came up with a study that showed who would do well on Ampligen. 30% of the people with ME/CFS had antibodies to spleen focus-forming virus (SFFV), and these were the patients who responded to Ampligen.

What we had found was a biomarker - the antibody to SFFV-env recognized by 7C10. This finding was later validated in the Lipkin multicenter study. The assay in our original paper was replicated in every study we did, but now all of that original data is lost. If I hadn't been so thoroughly discredited, and my research destroyed, Ampligen could have been approved.

But I look at it this way, if that Science paper on XMRV had never come out, would we have the research that is being done today?

Why did you call your book Plague?

One of the reasons we called it Plague was not so much because of the disease itself, but because of the increasing numbers we are seeing of people developing related health problems, such as autism, neuroimmune disease, and cancer. If we do nothing, in another decade one in two families will have one of these neuroimmune diseases.

From another standpoint, the title refers to the plague in science. There is a plague in medical research. We don't want to believe that medical research is corrupt. We don't want to think that if they saw a child who was sick, researchers wouldn't do something. But yet, the government is corrupting science – just as they did with ME/CFS and XMRV – by controlling the funding and the message, which ultimately determines what the journals publish.

What have we learned?

That is the question I ask myself.

XMRV was made in recombination with mouse cells. Before we could grow cells in labs we would pass cells through mice in order to attenuate them. But we found that by passing cancer cells through mice we could grow tumors; the cells had recombined with a retrovirus. Everyone before 1980 did this. It was standard laboratory procedure. We learned that anything we passed through animal tissues could make replication competent recombinant retroviruses in only ten days. All of our NIH research is based on mouse research. And those cell lines I worked with daily for more than 30 years have the potential to produce novel retroviruses.

So, here's the question: How many of these recombinant retroviruses are now in our environment and playing a role in all of these neuroimmune diseases?

If XMRV had mutated only two amino acids in its genetic envelope we could have had a true plague. Nobody could have predicted that XMRV could remain stable on a bench for months, or that it could be aerosolized and transmitted in dust, in saliva. But because our immune systems spotted it, we developed an antibody. (Many of the lab workers such as Max and myself seroconverted, meaning we developed the antibody from our lab exposure.)

How many people did we save by learning that XMRV could be aerosolized and spread to immune-compromised individuals or lab workers? We may have avoided something that could have infected everyone, because Silverman was sending XMRV all over the world.

But. exposing Silverman's XMRV as a lab artifact should not have ended the research. The work Frank Ruscetti and I did to find the epitope that the antibody recognizes in humans should have been completed. Currently 6% of the population carries an antibody that recognizes a gammaretrovirus envelope protein. Six percent is 20 million Americans!

Last year, Gary Owens published a research paper that showed the envelope protein of MLVs alone could cause vascular leak and aggressive tumors. He had previously published data identifying XMRV-2, now called B4RV, on November 10, 2009. That was only one month after our paper was published. We worked with Gary and found those sequences and proteins in some of our original patient samples. The virus Gary Owens found causes the very things I saw in Dan Peterson's patients and which are found in so many of the complex chronic diseases that affect our population today. So why was this work suppressed for three years, and why is it being downplayed now? How many new retroviruses have we created through all the mouse research, the vaccine research, gene therapy research? More importantly, how many new diseases have we created?

When they destroyed all of our work, and discredited everything I or Frank Ruscetti had ever published, and arranged for the publication of my mug shot in Science, the NIH very deliberately sent the message to researchers everywhere about what would happen to any honest scientist who dared ask those important questions.

If HHS gave you the power to re-name CFS, what would you call it?

Non-HIV AIDS. It is an acquired immune deficiency, beyond a shadow of a doubt.

Author

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About me:I'm a 25-year veteran of CFIDS. I know what it is like to be bedbound for long stretches of time. I also know what it is like to recover, and to relapse. But this blog is not about my personal experience. It is intended to be a resource - a collection of anything that might be helpful to the CFIDS community: book reviews, advice, CFIDS news, research, advocacy, opinion, who's who in our community, fundraising... and occasionally a bit of humor.

Disclaimer: I am not a doctor, which means nothing I write, no matter how sensible it may be, should be interpreted as medical advice.